We recently developed a transgenic mouse model of neurofibrillary tangle formation by expressing mutant tau (P301L). When this mouse model is crossed with mutant APP transgenic mice (Tg2576), the double transgenic progeny (TAPP) develop amyloid plaques and enhanced limbic NFT pathology. This is the only published mouse model to date that develops both amyloid plaques and tangles. More importantly the TAPP mice provide evidence that APP/Abeta interacts with tau to cause enhanced NFT pathology in vulnerable regions in these mice. In this proposal we aim to investigate the nature of this interaction and also to generate an improved tau/APP mouse model by crossing the tau(P301L) mice to TgCRND8 APP mice. The application has four Specific Aims: In Aim 1, we will investigate the accumulation of hyperphosphorylated tau in the TAPP mice to determine if activation of specific kinases might explain the enhanced limbic NFT pathology in these mice. In Aim 2, Ap vaccination will be used as a tool to prevent amyloid deposition in the TAPP mice to determine if AI3 clearance will also block cortico-limbic NFT formation. In Aim 3, we plan to replicate and extend our findings in the TAPP mice by crossing the tau(P301L) mice to a second mutant APP mouse, TgCRND8 (generated by Dr Westaway). The TgCRND8 mice develop amyloid deposition by 3 months of age and thus this tau/APP mouse model will determine if accelerated amyloid deposition will also cause accelerated and more extensive formation of cortico-limbic NFT pathology. Last in Aim 4, the tau(P301L)/TgCRND8 mice will be immunized with Abeta to determine if prevention and clearance of amyloid pathology will block NFT formation and improve cognitive function in mice with plaques and tangles.